Use of coumarin derivatives for the treatment of digestive tract disorders

ABSTRACT

A compound of the formulawherein W is H or a beta-D-glucopyranoslyloxy group, and Y and Z are independently H, C1-6 alkyl, or C1-6 alkoxy or a pharmacologically acceptable derivative thereof, is effective in the treatment or prophylaxis of a disorder benefitting from a decrease in the activity or concentration of transaminase enzymes, particularly liver disorders. The compound is preferably administered orally as a dietary supplement in combination with one or more of bee pollen, matricaria camomile, asperula oderata, royal jelly or honey.

This Application is a 371 of PCT/GB98/03169 filed Oct. 22, 1998.

The present invention relates to coumarin derivatives, particularlyhymecromone, to pharmaceutical compositions containing them and to theiruse in the treatment of disorders of the liver, kidney, pancreas,bladder and gastro-intestinal tract.

The liver is a complex organ with many diverse functions. It is thecentral organ of metabolism of carbohydrates, proteins, and fat. Itstores glycogen and takes part in regulating blood sugar, and storesother essential substances such as vitamins and factors concerned inhaemopoiesis. It synthesises fibrinogen, prothrombin, heparin, andplasma proteins, and is a site of destruction of deteriorated red bloodcells. It is also the chief detoxicating organ of the body renderingunwanted substances innocuous.

Viral hepatitis refers to infection of the liver caused by a group ofhepatitis viruses. Those so far identified are designated A, B, C, D andE. Other viruses such as Epstein-Barr virus and yellow fever virus maybe secondary causes of hepatitis and nonviral infections, drugs,chemicals and alcoholism may also cause hepatitis. One of the maintreatments for the various viral hepatitis infections is alpha or betainterferon, but in many cases it is not particularly effective. Otherdrugs that may produce a therapeutic response include lamivudine,ursodeoxycholic acid and vidarabine.

Primary biliary cirrhosis is a chronic liver disease of unknownaetiology, which develops due to progressive destruction of small andintermediate bile ducts within the liver, subsequently evolving tofibrosis and cirrhosis. Over 90% of patients are female, usually agedbetween 40 and 60 years. The disease is thought to be autoimmune innature, perhaps triggered by a micro-organism in the environment andmost patients exhibit autoantibodies to mitochondria. The disease isslowly progressive but no specific treatment is available.

Wilson's disease is due to an inborn error of liver metabolism leadingto the accumulation of toxic concentrations of copper. Gilbert'ssyndrome is an inherited disorder that affects the way bilirubin ishandled by the liver. Symptoms include mild jaundice, fatigue andabdominal pain. Again in both Wilson's disease and Gilbert's syndrome,there is no real effective treatment.

Accordingly there is a constant need for new compounds to treat thevarious liver disorders.

The inventor has now found that certain organic compounds (includingnaturally occurring extracts are effective in the treatment of variousliver and other disorders.

Accordingly in a first aspect of the invention there is provided use ofa compound of the Formula 2:

wherein:

W is H or a β-D-glucopyranosyloxy group,

X is OH, and

Y and Z are independently H, C₁₋₆ alkyl, or C₁₋₆ alkoxy andpharmacologically acceptable derivatives thereof in the manufacture of amedicament for the treatment or prophylaxis of a disease selected fromliver, kidney, pancreatic, bladder, and gastro-intestinal disorders anddisorders treatable by reducing the concentration or activity oftransaminase enzymes, said disease not being treatable with a cholereticor biliary antispasmodic agent.

Preferably Z is methyl.

Examples of known compounds covered by Formula 2 are. as follows: fraxin(7,8-dihydroxy-6-methoxycoumarin-8-β-D-glucoside), umbelliferone(7-hydroxycoumarin), skimmin (7-(glucosyloxy)coumarin), and hymecromone(7-hydroxy-4-methylcoumarin).

All compounds of Formula 2 are hereinafter referred to as “compounds ofthe invention”.

The compound that the inventor has done most work on and which has beenfound to be particularly effective is hymecromone (CAS Registry no.90-33-5).

Although hymecromone is primarily used for the fluorometricdetermination of enzyme activity (Clin. Chim. Acta., 39,49 (1972); Anal.Biochem., 54,40 (1973)) it is also known as a choleretic (agent whichaids the excretion of bile) and a biliary antispasmodic, and has beenadministered in doses of 300 mg-400 mg. (The Merck Index, 12th Edition,4903 and Martindale, The Extra Pharmacopoeia, 31st Edition p1715). Amore soluble form of hymecromone is disclosed in EP-A-0240874, andtablets of hymecromone for improving the excretion of bile are knownfrom U.S. Pat. No. 3,175,943. The choleretic and biliary antispasmodicactivity of hymecromone also is referred to in Petrioli (Fortschr. Med.1979 Jul. 5; 97 (25-26):1174-8) and U.S. Pat. No. 4,241,047.

Hymecromone is commercially available from ABCR GmbH & Co Kg (Karlsruhe,Germany, Acros organics (Geel, Belgium), Loba Feinchemie AG (Fischamend,Austria), Sigma-Aldrich Fine Chemicals (Poole, Dorset, UK). Hymecromoneis also available as a natural occurring extract of Manna Ash known asFraxin.

By pharmacologically acceptable derivatives of the compounds of Formula2, it is meant to include prodrugs, salts, solvates, esters, ethers,amides, glycosylated derivatives, and including methylated, aminated andacetylated derivatives.

By prodrug is meant any compound, which is capable of being metabolisedin vivo to give a compound of Formula 1.

By salt it is meant to include pharmaceutically acceptable salts derivedfrom an appropriate base such as alkali metal salts (e.g. sodium orpotassium), alkaline earth metals (e.g. magnesium or calcium), ammoniumand NX₄(wherein X is C₁₋₄ alkyl), or salzs of a hydrogen atom includingsalts formed from organic and inorganic acids such as those formed fromhydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric,lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric,maleic, xaloacetic, methanesulphonic, ethanesulphonic,ρ-toluenesulphonic, benzenesulphonic and isethionic acids.

The compounds of the invention, particularly hymecromone, havehepatoprotective and/or hepatoregenerative properties. Liver disorderswhich can be treated comprise hepatitis including infective hepatitis(e.g. viral hepatitis of types A, B, C, D and E), chronic activehepatitis, acute infective hepatitis, toxic hepatitis (e.g. as caused bydrugs and narcotics X-rays, solvents, chemotherapy, and alcohol abuse),steatosis hepatitis, acute parenchymatous hepatitis, amoebic hepatitis,cytomegalic hepatitis, enzootic hepatitis, familial hepatitis,homologous serum hepatitis, intestitial hepatitis, suppurativehepatitis, and trophopathic hepatitis. Various cirrhosis of the liverconditions which can be treated include primary and secondary biliarycirrhosis, alcoholic cirrhosis, annular cirrhosis, atrophic cirrhosis,bacterial cirrhosis, capsular cirrhosis, cardiac cirrhosis, fattycirrhosis lymphatic cirrhosis and pigmentary cirrhosis. Yet furtherliver disorders against which the compounds of the invention areeffective are Wilson's disease and Gilbert's svndrome.

The compounds of the invention are particularly effective in protectingthe liver from the toxic effects of anabolic steroids, alcohol,chemotherapy, solvents, drugs, and environmental pollution.

Early investigations also suggest that compounds of the invention suchas hymecromone will also be effective in the treatment or prophylaxis ofdisorders of the kidney (e.g. cirrhosis of the kidney), pancreas (e.g.pancreatitis), bladder and castrointestinal tract (e.g. cirrhosis of thestomach).

The invention can also be used to rejuvenate healthy people, especiallythose ex posed to heavy physical labour, the elderly a nd otherwis ehealthy people recovering from illness, and sportsmen (especially thoseusing anabolic steroids).

Without being bound by theory, it is thought that the corpounds of theinvention are at least partly effective by reducing the concentration oractivity in the peripheral blo od of transaminase enzymes, such as serumglutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase(AST), serum glutamic pyruvic transaminase (SGPT) or alaninetransaminase (ALT), and gamma glutamyl traospe)tidase (GGT).

The invention also provides a composition comprising a compound ofFormula 2 in combination with one or more of bee pollen, matricariacamomile, asperula oderata, royal jelly or honey.

The compositions may be presented in unit dose forms containing apredetermined amount of active ingredient per unit dose. Such a unit maycontain for example 50 mg to 2000 mg preferably 20 mg to 500 mgdepending on the condition being treated, the route of administrationand the age, weight and condition of the patient. In the case of acompound of the invention suspenuhed in hney, a unit dosage would berelative to on e or more spoonfuls of the honey. The patient shouldpreferably receive in the region of rug to 50 g per month,advantageously about 25 g to 28 g/month of a compound of the invention.Each unit dose may be administered once, twice, three or more timesdaily.

The compositions may be adapted for administration by any appropriateroute, for example by the oral (including buccal or sublingual), rectal,nasal, topical (including buccal, sublingual or transdermal), vaginal orparenteral (including subcutaneous, intramuscular, intravenous orintradermal) route. Such formulations may be prepared by any methodknown in the art of pharmacy, for example by bringing into associationthe active ingredient with the carrier(s) or excipient(s).

The compositions adapted for oral administration may be presented asdiscrete units such as capsules or tablets; powders or granules;solutions or suspensions in aqueous or non-aqueous liquids; edible foamsor whips; or oil-in-water liquid emulsions or water-in-oil liquidemulsions.

The compositions adapted forrectal administration may be presented assuppositories or enemas, and those adapted for vacinal administrationmay be presented as pessaries, tampons, creams, gels, pastes, foams orspray formulations.

The compositions adapted for parenteral administration include aqueousand non-aqueous sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blocd cf the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilised) condition reaucrind only the addition of the sterile liquid carrier, for example waterfor injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

Preferred unit dosage formulations are those containing a daily dose orsub-dose, as hereinabove recited, or an appropriate fraction thereof, ofan active ingredient.

In a preferred oral composition, a compound of the invention is presenttogether with one or more of the following other components preferablyat the given relative quantities:

More Preferred Preferred Component Range (g) Range (g) Compound of theinvention 15-30 25-28 (e.g. hymecromone) Bee Pollen 2 to 10 About 5Matricaria Camomile (Camomile) 2 to 10 About 5 pulv. Asperula Oderata(Sweet Woodruff) 2 to 10 About 5 pulv. Royal Jelly 5 to 15  About 10

The composition can be suspended in honey and presented as arejuvenating dietary supplement.

In a particularly preferred oral composition, there is provided acapsule containing from 100 to 300 mg (preferably about 210 mg) of acompound of the invention (e.g. hymecromone), from 3 to 7 mg (preferablyabout 5 mg) of camomile, and from 3 to 7 mg (preferably about 5 mg) ofbee pollen.

The preferred source of a Compound of the invention (hymecromone) isLoba Feinchemie AG (Fischamend, Austria);

The invention will now be illustrated by way of the following Examples.

EXAMPLE 1

A composition of the invention suspended in honey is as follows:

Ingredient Weight Bee Pollen 0.5 g Matricaria Camomile (Camomile) pulv.0.5 g Matricaria Camomile (Camomile) extr. sic. 2.5 g Asperula Oderata(Sweet Woodruff) pulv. 0.5 g Compound of the invention [Fraxinus Ornus2.0 g (Manna Ash) extr. sic.] Bee Honey 250.0 g

EXAMPLE 2

A further composition of the invention is as follows:

Ingredient Weight Bee Pollen 0.5 g Matricaria Camomile (Camomile) pulv.0.5 g Matricaria Camomile (Camomile) extr. sic. 0.5 g Asperula Oderata(Sweet Woodruff) pulv. 0.5 g Compound of the invention [4-Methyl-7- 5.0g hydroxycoumarin (hymecromone)] Royal Jelly 1.5 g Bee Honey 250.0 g

EXAMPLE 3

A composition of the invention according to Example 1 was administeredto 30 patients (20 males and 10 females) over a 3-month period.

During the three months of monitoring, the clinical diagnosis remainedconstant, however, changes were reported in the biochemical activity,evident in a reduction in enzymatic activities, SGOT (AST) and SGPT(ALT) in 70% of cases, as well as an improvement in symptomatic levels.In 65% of cases, fatigue and overall exhaustion were eliminated. Inpatients with chronic pancreatitis, pain in the area of the pancreasdisappeared and sexual instinct reappeared. During testing there were noharmful side effects present.

EXAMPLE 4

Patient A was diagnosed as having hypertrigliceridaemia. His liver wasincreased in size for 2p.p. of discrete ehogenous and homogenousparenhim (steatiosis hepatitis). He felt constantly tired, had chest andintestinal rumblings (especially after meals), complained of poordigestion (particularly stomach heaviness after any type of food), andexperienced repeated heartburn and belching.

Enzyme Levels: GGT: 90.0; SGPT: 41.3; SGOT: 33.8.

The patient was given a course of a composition of the inventionaccording to Example 1 at 2×5ml spoonfuls, 3 times per day for 40 days(hymecromone content equivalent to 140 mg/Sml spoonful or 25 gms permonth). The patient's transaminase levels were then measured again andwere found to have decreased as follows: GGT:40.3; SGPT:18.4; SGOT:21.

EXAMPLE 5

Patient B was diagnosed as having steatosis hepatitis (an early stage ofhepatitis). Liver size within normal, of ehogenous and homogenousparenhim, which indicates liver steatosis. The patient complained ofchronic pains below the right rib. After trying to digest food, heexperienced a bloated or heavy stomach and constant belching. He alsocomplained of occasional lethargy.

Biochemical Analysis: GGT:220; SGPT:110; SGOT:65.

After a course of a composition of the invention as in Example 1, thesteatosis hepatitis was found to be in regression. The patient'stransaminase enzyme levels also decreased as follows: GGT:146;SGPT:26.2; SGOT:24.2.

EXAMPLE 6

Patient C was diagnosed as having laesio hepatitis diffusa chr. andhepatomegalia. The patient had suffered from liver problems for sometime, he felt depressed and tired, had a high fever and was jaundiced.He had an enlarged liver of hyperehogenous and inhomogenous parenhim,indicating chronic diffused liver lesion.

Biochemical Analysis: GGT:685; SGPT:113; SGOT:124.

After a course of a composition of the invention as in Example 1, thepatient's transaminase enzyme levels decreased as follows: GGT:57;SGPT:27.3; SGOT:23.9.

EXAMPLE 7

The preparation of Example 2 was used in the treatment of severalpatients suffering from various kinds of liver disease, some veryadvanced, but in all cases showing high levels of enzymes, particularlytransaminase enzymes.

In all cases, the patients received the preparation of the invention inaddition to the standard treatments (e.g. B-vitamins, K-vitamins,Paraaminometilbenzoic acid, fursemid, aldactone, propranolol andothers). Pains found under the right ribs, bend, fatigue and generalexhaustion were the predominant complaints of the patients.

Liver Profile, Blood Analysis and general health conditions weremonitored on a monthly basis.

The following enzymes were measured in the biochemical analysis:

Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartateaminotransferase (AST): (NORMAL VALUE: 10 to 40 international units perdecilitre);

Serum Glutamic Pyruvic Transaminase (SGPT) or alanine transaminase(ALT): (NORMAL VALUE: 10 to 30 international units per decilitre);

Gamma Glutamyl Transpeptidase (GGT): (NORMAL VALUE: 0-45 internationalunits per decilitre).

On the basis of the biochemical determination, the patients wereclassified into four groups.

GROUP 1: Patients diagnosed with: cirrhosis and chronic activehepatitis, with high transaminase (AST [SGOT] & ALT [SGPT] over 120);

GROUP 2: Patients diagnosed with: viral hepatitis (chronic), both B andC chronic type in active state (AST [SGOT] and ALT [SGPT] over 200);

GROUP 3: Patients diagnosed with: toxic alcoholic liver lesion in acutestate, with high transaminase (AST [SGOT] and ALT [SGPT] over 350),acute alcoholic hepatitis;

GROUP 4: Patients diagnosed with: syndromes and high transaminase.

In summary, the patients, who were using the composition of theinvention for more than two months in conjunction with standard therapy,recovered quicker and felt much better. In addition to an improvedgeneral state of health, the patients reported improvements in appetiteand physical fitness.

The biochemical analysis showed a rapid reduction of blood transaminase(AST [SGPT] and ALT [SGOT] to 100 units or less.

Patients in the first (1) third (3) and fourth (4) group respondedbetter and quicker when using the invention and the transaminase fellquickly to between 60 and 80.

The patients in the second (2) group, those with chronic B or Chepatitis, whether receiving Interferon or not, responded slower.Initially there was no physical signs of improvement, but after a time areduction in transaminase concentration in blood (AST [SCOT] and ALT[SGPT]), was noticed concomitant with regression of the disease.

EXAMPLE 8

The hepatoprotective effect of a composition in accordance with theinvention was investigated in mice with acetaminophen (paracetamol)induced hepatotoxicity.

CBA/H Zgr inbred mice were raised in an animal colony unit. Mice of bothsexes aged 3 to 4 month were used in the experiments. Mice weremaintained under standard laboratory conditions, fed with commerciallyavailable murine food pellets and allowed water ad libitum.

The procedure of Guarner was followed (see Hepatology 1988; 3:248-53).To induce hepatic drug-metabolising enzymes, mice were givenphenobarbitone-sodium in drinking water for 7 days (0.3 g/L).Thereafter, mice were fasted overnight.

Three different doses (10, 50 or 250 mg/kg) of a Composition of theinvention (Hymecromone) were given to mice intraperitoneally in volumesof 0.5 ml 30 minutes before intragastric administration of acetaminophen(300 mg/kg).

The above ingredients were dissolved in phosphate buffered saline (PBS)to which several drops of Tween 20™ (polyoxyethylene 20 sorbitanmonolaurate) were added (50 μl/ml). The resulting white milk suspensionwas administered to mice intraperitoneally.

At the same time, control animals were given 0.5 ml of pyrogen-freesaline to which several drops of Tween 20™ (50 μl/ml) were added.

Acetaminophen, dissolved in heated PBS, was given intragastrically, bystomach tube, in a volume of 0.5 ml. Animals were allowed food 4 hourslater. Mortality of mice was followed for 48 hours, as previous resultshave shown that control mice (given saline rather than the compositionbefore acetaminophen) either die within this period or fully recover andsurvive indefinitely.

Plasma aspartate aminotransferase (AST) and alanine aminotransferase(ALT) were measured 24 hours after the administration of acetaminophen,because it has been observed that the levels of AST and ALT are at theirpeak values at this time. Mice were given 250 units of Hymecromoneintraoeritoneally 15 minutes before bleeding. Blood was obtained bypuncture of medial orbital angle using glass capillary tubes. Plasma wasstored at −20° C. until aminotransferase determination, which wascarried out using standard laboratory techniques (see Expert Panel onEnzymes, Committee on Standards, Clin. Chem. Biochem. 1977; 15: 39-51and Clin. Chem. Acta. 1980; 105: 147F-54F).

Differences in survival between groups of mice were compared by χ²-test.Plasma AST and ALT concentrations are expressed as means±SEM anddifferences between groups were compared by Student's t-test.

Table 1 shows the mortality of mice 48 hours after acetaminophenadministration. In comparison with the control group of mice givensaline, pretreatment of mice with 250 mg/kg of Hymecromone significantlyreduced the mortality of mice (P<0.01). The mortality of mice given 10or 50 mg/kg of the composition was similar to that observed in controlmice given saline. Tables 2 and 3 show the mortality of mice of twofurther experiments. As shown, pretreatment of mice with Hymecromone(250 mg/kg) statistically significantly reduced the mortality of mice incomparison with control mice given saline (P<0.001).

TABLE 1 The effect of different doses of Hymecromone on survival of micewith AAP-induced hepatotoxicity Dose of Hymecromone No of dead mice/Treatment^(a) (mg/kg) Total No of mice (%)^(b) Saline + AAP — 13/13(100) Hymecromone + 10 12/12 (100) AAP Hymecromone + 50 11/12 (92)  AAPHymecromone + 250   2/7 (29)^(c) AAP ^(a)Mice were given 300 mg/kg AAPintragastrically in volume of 0.5 ml. Saline or different doses ofHymecromone were given intraperitoneally 30 minutes before AAPadministration ^(b)Mortality was recorded 48 hours after AAPadministration ^(c)Significantly different in relation to the controlgroup of mice treated with saline (P < 0.01)

TABLE 2 The effect of different doses of Hymecromone on survival of micewith AAP-induced hepatotoxicity Dose of Hymecromone No of dead mice/Treatment^(a) (mg/kg) Total No of mice (%)^(b) Saline + AAP — 10/13 (77)Hymecromone + 50 9/13 (93) AAP Hymecromone + 250 0/13 (0)^(c) AAP^(a)Mice were given 250 mg/kg AAP intragastrically in volume of 0.5 ml.Saline or Hymecromone were given intraperitoneally 30 minutes before AAPadministration. ^(b)Mortality was recorded 48 hours after AAPadministration. ^(c)Significantly different in relation to the controlgroup of mice treated with saline (P < 0.001).

TABLE 3 The effect of Hymecromone on survival of mice with AAP-inducedhepatotoxicity No of dead mice/ Treatment^(a) Total No of mice (%)^(b)Saline + AAP 16/16 (100) Hymecromone + AAP 0/15 (0)^(c) ^(a)Mice weregiven 250 mg/kg AAP intragastrically in volume of 0.5 ml. Saline orHymecromone (250 mg/kg) were given intraperitoneally 30 minutes beforeAAP administration. ^(b)Mortality was recorded 48 hours after AAPadministration. ^(c)Significantly different in relation to the controlgroup of mice treated with saline (P < 0.001)

EXAMPLE 9

The effect of a Compound of the invention (Hymecromone) was investigatedon plasma aminotransferase levels in mice with AAP-inducedhepatotoxicity.

Hymecromone (250 mg/kg) or a control of saline was given to mice 30minutes before administration of acetaminophen (220 mg/kg). Plasma ASTand ALT were measured 24 hours after acetaminophen administration. Table4 shows plasma aminotransferase levels in normal and in mice treatedwith Hymecromone or saline. As shown, in comparison with normal mice,the administration of acetaminophen increased AST and ALT byapproximately 19 and 100 times, respectively. Pretreatment of mice withthe composition significantly reduced the increase of AST and ALT incomparison with control mice pretreated with saline (AST five times andALT three times; P<0.005).

TABLE 4 Plasma aminotransferase levels in mice with AAP-inducedhepatotoxicity pretreated with saline or Hymecromone Treatment^(a) AST(U/L)^(b) ALT(U/L)^(b) Normal mice 75 ± 4 23 ± 1 (n = 19) (n = 19)Saline + AAP 1417 ± 355 2300 ± 376 (n = 16) (n = 16) Hymecromone + 267 ±56^(c) 776 ± 166^(c) AAP (n = 16) (n = 16) ^(a)Saline or Hymecromone(250 mg/kg) were given 30 minutes before AAP administration (220 mg/kg)^(b)Determined 24 hours after AAP administration; mean ± SEM^(c)Significantly different in relation to the control group of micegiven saline before AAP administration (P < 0.005)

The results of the investigation have shown that the composition inaccordance with the invention has hepatoprotective effect in mice withacetaminophen-induced acute hepatotoxicity. The composition in a dose of250 mg/kg given intraperitoneally to mice 30 minutes beforeadministration of acetaminophen, significantly reduced the mortality ofmice and reduced plasma aminotransferase levels in comparison withcontrol mice given saline before administration of acetaminophen.

The invention is therefore very effective in the treatment of differentkinds of liver, kidney, pancreatic and gastrointestinal disorders. Itreduces the transaminase levels in peripheral blood, and reduces theactivity and aggressiveness of the illness.

What is claimed is:
 1. A method for the treatment of hepatotoxicity notbeing accompanied by a deficiency in bile excretion or biliary spasms,in a patient having hepatoxicity not accompanied by a deficiency in bileexcretion or biliary spasms, which method comprises administering tosaid patient a transaminase enzyme reducing amount of a compound ofFormula 2:

wherein: W is H or a β-D-glucopyranosyloxy group; and Y and Z areindependently H, C₁₋₆ alkyl or C₁₋₆ alkoxy; or pharmacologicallyacceptable derivatives thereof.
 2. A method according to claim 1,wherein the compound of Formula 2 is hymecromone.
 3. A method for thetreatment of liver disorders treatable by a decrease in the activity orconcentration of transaminase enzymes, said disorders not beingaccompanied by a deficiency in bile excretion or biliary spasms, in apatient having a liver disorder treatable by a decrease in the activityor concentration of transaminase enzymes not accompanied by a deficiencyin bile excretion or biliary spasms, which method comprisesadministering to said patient a transaminase enzyme reducing amount of acompound of Formula 2:

wherein: W is H or a β-D-glucopyranosyloxy group; and Y and Z areindependently H, C₁₋₆ alkyl or C₁₋₆ alkoxy; or pharmacologicallyacceptable derivatives thereof.
 4. A method according to claim 3,wherein the compound of Formula 2 is hymecromone.
 5. A method accordingto claim 4, wherein the liver disorder is resultant from chemotherapy.6. A method according to claim 4, wherein the liver disorder iscirrhosis.
 7. A method according to claim 4, wherein the liver disorderis hepatitis.
 8. A method for the treatment of disorders treatable by adecrease in the activity or concentration of transaminase enzymes, saiddisorders not being accompanied by a deficiency in bile excretion orbiliary spasms, in a patient having a disorder treatable by a decreasein the activity or concentration of transaminase enzymes not accompaniedby a deficiency in bile excretion or biliary spasms, which methodcomprises administering to said patient a transaminase enzyme reducingamount of a compound of Formula 2:

wherein: W is H or a β-D-glucopyranosyloxy group; and Y and Z areindependently H, C₁₋₆ alkyl or C₁₋₆ alkoxy; or pharmacologicallyacceptable derivatives thereof.
 9. A method according to claim 8,wherein the compound of Formula 2 is hymecromone.